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Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1.Objectives: To describe characteristics and outcomes of PH-NF...

Resume Le dispositif s’assistance ventriculaire gauche est utilise de maniere definitive (destination therapy, DT) chez les patients en insuffisance cardiaque chronique contre-indiques a la greffe du fait de l’âge et/ou des co-morbidites associees. Compare au traitement medical, cette therapeutique definitive – vue comme un traitement palliatif – ameliore la survie, la qualite de vie et le statut fonctionnel des patients correctement selectionnes. Cependant, les complications du dispositif d’assistance ventriculaire gauche peuvent compromettre la qualite de vie et influencer largement l’evolution vers une fin de vie attendue, posant des lors de nombreuses questions ethiques (par exemple : arret de machine) qui deviendront plus complexes quand l’experience des equipes et des patients sera plus grande. Ces questions ethiques devront se poser dans la pratique clinique tres precocement, pour permettre de prevenir des conflits lies a la prise en charge de ces patients engages dans un tel programme. Dans cet article, nous defendons l’idee qu’une implication precoce des equipes de soins palliatifs, au sein d’une equipe multidisciplinaire centree sur le patient et ses proches, pourrait permettre d’anticiper les complications liees a la machine, de preparer l’evolution clinique vers la fin de vie ou un arret de machine sera necessaire et parfois demande par le patient ou les proches.

A 70-year-old woman, with a past medical history of permanent atrial fibrillation, cholecystectomy for symptomatic gallstones and obesity (54 kg/m² body mass index), was admitted to the hospital for rapidly increasing dyspnea (NYHA class III). At admission, heart rate was 110 beats per minute (bpm) and blood pressure was 125/73 mmHg. Physical examination revealed clinical signs of right heart failure including major peripheral oedema, hepatomegaly, bilateral pleural effusion, and ascites with no signs of portal hypertension or hepatocellular insufficiency.

International audience; AIMS: Increased left ventricular wall thickness (LVWT) is a common finding in cardiology. It is not known how often hereditary transthyretin-related familial amyloid cardiomyopathy (mTTR-FAC) is responsible for LVWT. Several therapeutic modalities for mTTR-FAC are currently in clinical trials; thus, it is important to establish the prevalence of TTR mutations (mTTR) and the clinical characteristics of the patients with mTTR-FAC. METHODS AND RESULTS: In a prospective multicentre, cross-sectional study, the TTR gene was sequenced in 298 consecutive patients diagnosed with increased LVWT in primary cardiology clinics in France. Among the included patients, median (25-75th percentiles) age was 62 [50;74]; 74% were men; 23% were of African origin; and 36% were in NYHA Class III-IV. Median LVWT was 18 (16-21) mm. Seventeen (5.7%; 95% confidence interval [CI]: [3.4;9.0]) patients had mTTR of whom 15 (5.0%; 95% CI [2.9;8.2]) had mTTR-FAC. The most frequent mutations were V142I (n = 8), V50M (n = 2), and I127V (n = 2). All mTTR-FAC patients were older than 63 years with a median age of 74 [69;79]. Of the 15 patients with mTTR-FAC, 8 were of African descent while 7 were of European descent. In the African descendants, mTTR-FAC median age was 74 [72;79] vs. 55 [46;65] years in non-mTTR-FAC (P \textless 0.001). In an adjusted multivariate model, African origin, neuropathy, carpal tunnel syndrome, electrocardiogram (ECG) low voltage, and late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging were all independently associated with mTTR-FAC. CONCLUSION: Five per cent of patients diagnosed with hypertrophic cardiomyopathy have mTTR-FAC. Mutated transthyretin genetic screening is warranted in elderly subjects with increased LVWT, particularly, those of African descent with neuropathy, carpal tunnel syndrome, ECG low voltage, or LGE

International audience; Background: We have been intrigued by the observation that aortic stenosis (AS) may be associated with characteristic features of mitral drug-induced valvular heart disease (DI-VHD) in patients exposed to valvulopathic drugs, thus suggesting that beyond restrictive heart valve regurgitation, valvulopathic drugs may be involved in the pathogenesis of AS. Methods: Herein are reported echocardiographic features, and pathological findings encountered in a series of patients suffering from both AS (mean gradient > 15 mm Hg) and mitral DI-VHD after valvulopathic drugs exposure. History of rheumatic fever, chest radiation therapy, systemic disease or bicuspid aortic valve disease were exclusion criteria. Results: Twenty-five (19 females, mean age 62 years) patients having both AS and typical features of mitral DI-VHD were identified. Mean transaortic pressure gradient was 32+/-13 mm Hg. Aortic regurgitation was >= mild in 24 (96%) but trivial in one. Known history of aortic valve regurgitation following drug initiation prior the development of AS was previously diagnosed in 17 patients (68%). Six patients underwent aortic valve replacement and 3 both aortic and mitral valve replacement. In the 9 patients with pathology analysis, aortic valvular endocardium was markedly thickened by dense non-inflammatory fibrosis, a characteristic feature of DI-VHD. Conclusion: The association between AS and typical mitral DI-VHD after valvulopathic drug exposure may not be fortuitous. Aortic regurgitation was usually associated to AS and preceded AS in most cases but may be lacking. Pathology demonstrated the potential role of valvulopathic drugs in the development of AS. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Risk stratification in advanced heart failure (HF) is crucial for the individualization of therapeutic strategy, in particular for heart transplantation and ventricular assist device implantation. We tested the hypothesis that cardiac gene expression profiling can distinguish between HF patients with different disease severity. We obtained tissue samples from both left (LV) and right (RV) ventricle of explanted hearts of 44 patients undergoing cardiac transplantation or ventricular assist device placement. Gene expression profiles were obtained using an in-house microarray containing 4217 muscular organ-relevant genes. Based on their clinical status, patients were classified into three HF-severity groups: deteriorating (n= 12), intermediate (n= 19) and stable (n= 13). Two-class statistical analysis of gene expression profiles of deteriorating and stable patients identified a 170-gene and a 129-gene predictor for LV and RV samples, respectively. The LV molecular predictor identified patients with stable and deteriorating status with a sensitivity of 88% and 92%, and a specificity of 100% and 96%, respectively. The RV molecular predictor identified patients with stable and deteriorating status with a sensitivity of 100% and 96%, and a specificity of 100% and 100%, respectively. The molecular prediction was reproducible across biological replicates in LV and RV samples. Gene expression profiling has the potential to reproducibly detect HF patients with highest HF severity with high sensitivity and specificity. In addition, not only LV but also RV samples could be used for molecular risk stratification with similar predictive power.

Resume Les etudes epidemiologiques ont permis de montrer l’augmentation importante et constante de la prevalence de l’insuffisance cardiaque, mais aussi la modification du profil des patients parallelement aux progres therapeutiques, technologiques intervenus dans le traitement des pathologies cardiovasculaires. Une nouvelle entite a ainsi a ete identifiee decrite en particulier chez les sujets âges : l’insuffisance cardiaque a fraction d’ejection preservee. Cette pathologie reste mal identifiee, mais ses specificites cliniques et son pronostic, ont pu etre precises, alors que le traitement de fond reste tres discute. Pour l’insuffisance cardiaque avec dysfonction systolique, les progres pharmacologiques et techniques, ont permis de reduire la mortalite globale et subite, et d’allonger la survie, avec pour corollaire une augmentation du nombre de cas d’insuffisance cardiaque avancee, et d’hospitalisations pour insuffisance cardiaque aigue. Les progres de la chirurgie cardiaque, de la cardiologie interventionnelle expliquent en partie ces evolutions. Parallelement les traitements medicamenteux ont evolue passant des diuretiques et digitaliques a l’utilisation des antagonistes neurohormonaux dont l’impact sur la survie et la qualite de vie a ete determinant. La miniaturisation et l’amelioration des performances des stimulateurs cardiaques et des defibrilllateurs ont aussi participe a ce succes. L’angiographie, l’echocardiographie, l’imagerie par resonance magnetique (IRM) et le BNP (Brain Natriuretic Peptide) ont transforme la prise en charge au quotidien, ameliore la comprehension de la physiopathologie et mis en evidence le role essentiel du remodelage cardiaque et vasculaire. Malheureusement les patients restent confrontes a l’echappement au traitement precoce ou tardif. La prise en charge globale favorisant l’observance par les patients et l’application des recommandations permettent d’ameliorer la qualite de vie et la survie et d’inflechir le cout economique majeur de cette maladie chronique. Les nouvelles approches pharmacologiques sont donc essentielles et les etudes des nouveaux inotropes (activateurs de la myosine, modulateurs du metabolisme energetique), des nouvelles classes d’aquaretiques et de diuretiques, de meme que des nouveaux systemes d’assistance circulatoire ou de coeur implantable seront determinantes.

Background— Myxomatous dystrophy of the cardiac valves affects ≈3% of the population and remains one of the most common indications for valvular surgery. Familial inheritance has been demonstrated with autosomal and X-linked transmission, but no specific molecular abnormalities have been documented in isolated nonsyndromic forms. We have investigated the genetic causes of X-linked myxomatous valvular dystrophy (XMVD) previously mapped to chromosome Xq28. Methods and Results— A familial and genealogical survey led us to expand the size of a large, previously identified family affected by XMVD and to refine the XMVD locus to a 2.5-Mb region. A standard positional cloning approach identified a P637Q mutation in the filamin A ( FLNA ) gene in all affected members. Two other missense mutations (G288R and V711D) and a 1944-bp genomic deletion coding for exons 16 to 19 in the FLNA gene were identified in 3 additional, smaller, unrelated families affected by valvular dystrophy, which demonstrates the responsibility of FLNA as a cause of XMVD. Among carriers of FLNA mutation, the penetrance of the disease was complete in men and incomplete in women. Female carriers could be mildly affected, and the severity of the disease was highly variable among mutation carriers. Conclusions— Our data demonstrate that FLNA is the first gene known to cause isolated nonsyndromic MVD. This is the first step to understanding the pathophysiological mechanisms of the disease and to defining pathways that may lead to valvular dystrophy. Screening for FLNA mutations could be important for families affected by XMVD to provide adequate follow-up and genetic counseling.

BackgroundHeart failure (HF) symptoms, related to pulmonary capillary hypertension, are frequent in hypertrophic cardiomyopathy (HCM). Pulmonary hypertension (PH) is the consequence of left ventricular (LV) diastolic pressure elevation and/or functional mitral regurgitation. We aimed to evaluate determinants and prognostic significance of rest and exercise PH in HCM.Methods and ResultsWe included 235 patients referred for clinical work-up of HCM. Rest pulmonary artery systolic pressure (PASP) was measurable in 214 (91%) patients (48±16 years, 161 males). A symptom-limited semi-supine bicycle exercise was carried out in 188 patients. PASP was measurable during exercise in 108 patients (57%). Resting PH (≥36mm Hg) was present in 56 patients (26.2%) and exercise PH (≥60mm Hg) in 38 patients (35.2%). Mutivariate correlates of rest PASP were sinus rhythm (β= –0.15, P=0.021), LV obstruction tract (LVOT) peak gradient (β= 0.22, P=0.001) and left atrial volume (β= 0.39, P

Background Right ventricle failure (RVF) is a frequent and severe complication after cardiac transplantation. However, risk stratification for RVF is poorly achieved. Development of transcriptomic biomarkers for outcome prediction in cardio-vascular diseases is promising. Aim To identify right ventricular gene expression signature associated to RVF and to define a transcriptomic biomarker that could predict post-transplantation RVF. Methods Recipient RV myocardial samples of 44 patients transplanted from February 1998 to November 2002 in our center were collected. We retrospectively identified patients with (RVF group) and without (CTL group) post-transplantation RVF. A 4035-gene expression profile was obtained for all patients. Differentially expressed genes between RVF and CTL groups were identified and a molecular RVF predictor was used to determine for each patient a RVF prediction score (RVFs). Results 9 (20%) and 18 (41%) patients were classified in RVF and CTL groups respectively. As compared to CTL group, RVF patients showed higher pre-operative bilirubin level and higher post-operative death rate. Molecular RVF predictor included 75 differentially expressed genes. Using this predictor, risk for post-transplantation RVF was 2.8-fold greater if RVFs was >0.5 (CI 95%: 1.243-6.305). Sensitivity and specificity of RVFs were 0.778 and 0.889, respectively. Using receiver operating characteristic analysis, RVFs area under curve (AUC) was significantly greater than AUC of commonly used RVF predictors (pulmonary vascular resistance, trans-pulmonary gradient). Conclusion Gene expression profiling of recipient right ventricle could be used to predict post-transplantation RVF. Transcriptomic biomarkers should be further investigated as a new tool for selection of cardiac transplant candidates.

Introduction: Right ventricle failure (RVF) is a frequent and severe complication after cardiac transplantation. However, risk stratification for RVF is poorly achieved. Development of transcriptomic biomarkers for outcome prediction in cardio-vascular diseases is promising. Hypothesis: Our aim was to identify right ventricular gene expression signature associated to RVF and to define a transcriptomic biomarker that could predict post-transplantation RVF. Methods: Recipient RV myocardial samples of 44 patients transplanted from February 1998 to November 2002 in our center were collected. We retrospectively identified patients with (RVF group) and without (CTL group) post-transplantation RVF. A 4035-gene expression profile was obtained for all patients. Differentially expressed genes between RVF and CTL groups were identified and a molecular RVF predictor was used to determine for each patient a RVF prediction score (RVFs). Results: 9 (20%) and 18 (41%) patients were classified in RVF and CTL groups respectively. As compared to CTL group, RVF patients showed higher pre-operative bilirubin level and higher post-operative death rate. Molecular RVF predictor included 75 differentially expressed genes. Using this predictor, risk for post-transplantation RVF was 2.8-fold greater if RVFs was >0.5 (CI 95%: 1.243-6.305). Sensitivity and specificity of RVFs were 0.778 and 0.889, respectively. Using receiver operating characteristic analysis, RVFs area under curve (AUC) was significantly greater than AUC of commonly used RVF predictors (pulmonary vascular resistance, trans-pulmonary gradient). Conclusions: Gene expression profiling of recipient right ventricle could be used to predict post-transplantation RVF. Transcriptomic biomarkers should be further investigated as a new tool for selection of cardiac transplant candidates.

International audience

OBJECTIVES The purpose of this study was to describe the phenotypic characteristics of an inherited myxomatous valvular dystrophy mapped to Xq28. BACKGROUND Myxomatous valve dystrophies are a frequent cause of valvular diseases, the most common being idiopathic mitral valve prolapse. They form a group of heterogeneous diseases difficult to subclassify. The first mapping of the gene for a myxoid valvular dystrophy to Xq28 allowed investigation of the phenotype of affected members in a large family and characterization of the disease. METHODS Among the 318 members in the pedigree, 89 agreed to participate in this study. Phenotypic characteristics were investigated using clinical examination, transthoracic echocardiography and biological analysis (F.VIII activity). Genetic status was based on haplotype analysis. RESULTS Among 46 males, 9 were hemizygous to the mutant allele and had an obvious mitral and/or aortic myxomatous valve defect, and 4 had undergone valvular surgery. All had typical mitral valve prolapse associated in six cases with moderate to severe aortic regurgitation. The valve defect cosegregated with mild hemophilia A (F.VIII activity = 0.32 ± 0.05). The 37 remaining males had normal valves and normal F.VIII activity. Heterozygous women were identified on the basis of their haplotypes. Among the 17 women heterozygous to the mutant allele, moderate mitral regurgitation was present in 8, associated with mild mitral valve prolapse in 1 and aortic regurgitation in 3, whereas 2 women had isolated mild aortic regurgitant murmur. In heterozygotes, the penetrance value was 0.60 but increased with age. CONCLUSION X-linked myxomatous valvular disease is characterized by mitral valve dystrophy frequently associated with degeneration of the aortic valves affecting males and, to a lower severity, females. The first localization of a gene for myxomatous valvular diseases is the first step for the subclassification of these diseases.

BackgroundHeart failure (HF) symptoms, related to pulmonary capillary hypertension, are frequent in hypertrophic cardiomyopathy (HCM). Pulmonary hypertension (PH) is the consequence of left ventricular (LV) diastolic pressure elevation and/or functional mitral regurgitation. We aimed to evaluate determinants and prognostic significance of rest and exercise in HCM.Methods and resultsWe included 235 patients referred for clinical work-up of HCM. Rest pulmonary artery systolic pressure (PASP) was measurable in 214 (91%) patients (48±16 years, 161 males). A symptom-limited semi-supine bicycle exercise was carried out in 188 patients. PASP was measurable during exercise in 108 patients (57%). Resting PH (≥36mmHg) was present in 56 patients (26.2%) and exercise PH (≥60mmHg) in 38 patients (35.2%). Mutivariate correlates of rest PASP were sinus rhythm (β=–0.15, P=0.021), LV obstruction tract (LVOT) peak gradient (β=0.22, P=0.001) and left atrial volume (β=0.39, P

Purpose FDG-positron emission tomography (PET) has high diagnostic accuracy in cardiac sarcoidosis (CS). Beyond CS, the non invasive diagnosis of inflammatory cardiomyopathies (IC) is challenged by a lower diagnostic performance of usual tools as magnetic resonance imaging (MRI). Methods 17 consecutive patients with suspected IC had a FDG-PET to detect myocardial inflammation. From all clinical data including PET, we classified patients in either CS or non-CS and respective PET data were compared. The clinical impact of adding PET in the non-CS group was evaluated by comparing diagnosis and management proposed by an expert blind to PET with final diagnosis and management actually held in practice. Results 6 patients had CS, all with positive PET. In the 11 non-CS patients, 7 had a positive PET. All had MRI late gadolinium enhancement in FDG uptake areas, suggesting a true positivity of PET for the presence of inflammation. PET data were all significantly different between CS and nonCS patients with positive PET, particularly the coefficient of variation of cardiac SUV which is an index of heterogeneity of FDG uptake was significantly greater in CS patients (0,4 vs 0,17 p Conclusion Some patients with suspected IC had a positive FDG-PET in favour of myocardial inflammation, with a different pattern from that observed in CS. Adding PET to usual diagnostic tools led to a decrease of possible IC diagnosis that turned in excluded IC. These preliminary data suggest a potential role of PET for the non-invasive diagnosis of IC that will need further investigations. Download : Download high-res image (89KB) Download : Download full-size image Abstract 0049 – Figure: FDG uptake concordant with MRI-LGE

International audience; Progress in the medical treatment of patients with heart failure with systolic dysfunction, cardiac resynchronization therapy, internal cardiac defibrillators and multidisciplinary management programmes has resulted in dramatic improvements in survival and quality of life; however, this progress has led to an increase in the prevalence of advanced heart failure. In the context of organ shortage for cardiac transplantation, the technological developments in left ventricular assist devices, shown in recent positive clinical studies, provide real hope for patients with advanced heart failure. This article summarizes the most recent clinical studies concerning left ventricular assist devices and discusses for whom and when a left ventricular assist device should be proposed.

Introduction: Out of proportion post-capillary pulmonary hypertension (resulting from left-sided heart failure, group 2 of the World Health Organisation of Pulmonary Hypertension (PH) classification.) is a well known hemodynamic entity described in the past in mitral stenosis, but also concern patients with leftside heart failure and preserved ejection fraction (HFpEF). The prevalence is probably underestimated because a part of this population is addressed to the PH center and misdiagnosed group 1 PH of WHO classification.

Epidemiological studies have pointed out the continuous and significant increase of heart failure prevalence as well as the change of the patients profile in relation to therapeutic and technological improvement in the treatment of cardiovascular diseases. A new entity has thus been identified especially among the elderly: heart failure with preserved ejection fraction. This pathology is still not well identified, although its clinical specifications and its prognosis have been specified, as some uncertainties concerning the disease-modifying drug remain. Concerning systolic heart failure, progress in pharmacological treatments and in medical devices has lead to a decrease in sudden death and to a lengthening of survival duration, while both advanced heart failure and hospitalization for acute heart failure rates are increasing. Progress in cardiac surgery, and interventional cardiology partly explains these evolutions. At the same time, pharmacological treatments such as diuretics and digitalics have been replaced by neurohormonal antagonists with an obvious impact on survival and quality of life. Size reduction and performance improvements of pace makers and defibrillators have been determining for this progress.Angiography, echography, RMN (Resonnance Magnetic Nuclear) and BNP (Brain Natriuretic Peptide) dosage have modified daily therapeutic recommendations, improved pathophysiological understanding and pointed out the major role of cardiac and vascular remodelling. Unfortunately, patients are still confronted with an initial or chronic treatment failure. Heart failure management programmes, taking into account patient observance and guidelines implementation, allows the improvement of the quality of life, survival and the decrease of the major costs related to this chronic illness. New pharmacological approaches, especially inotropic drugs(myosin activators, energetic metabolism modulators), new aquaretic and diuretic drugs and even new left ventricular assistance devices or implantable artificial heart are thus essential.

Aims This study was designed to compare the specific effects of two heart rates (HR), 55 and 75 b.p.m., in patients with heart failure (HF). Methods and results Patients with chronic HF, left ventricular ejection fraction (LVEF) ≤ 35%, and a pacemaker with >90% of paced QRS, were included in a randomized cross-over trial of two 3-month periods where pacing rate was set at either 55 or 75 b.p.m. At the end of each period, patients were examined and radionuclide ventriculography, echocardiography, and blood sampling were performed for centralized and blinded analysis. Two patients did not complete the study because of early worsening while paced at 75 b.p.m. Twelve patients completed the study. Compared with 75 b.p.m., pacing at 55 b.p.m. was associated with a higher LVEF [+4.7% (2.6–6.7), P < 0.001], lower B-type natriuretic peptide levels [−91 pg/mL (−148 to −33), P < 0.01], lower systolic pulmonary artery pressure (41 ± 10 vs. 47 ± 10 mmHg, P = 0.02) and lower NYHA (New York Heart Association) class (2.2 ± 0.6 vs. 2.6 ± 0.5, P = 0.03). The baseline pacing rate prior to inclusion had no effect on results. Conclusion HR per se may impact cardiac function and low HR might be beneficial in patients with systolic HF compared with intermediate HR.

Objectives The study was conducted to determine the long-term outcome of patients who underwent heart transplantation 15 to 20 years ago, in the cyclosporine era, and identify risk factors for death. Methods A retrospective analysis was done of 148 patients who had undergone heart transplantation between 1985 and 1991 at a single center. Operative technique and immunosuppressive treatment were comparable in all patients. Results Actuarial survival rates were 75% (n = 111), 58% (n = 86), and 42% (n = 62) at 5, 10, and 15 years, respectively. The mean follow-up period was 12.1 ± 5.6 years for patients who survived more than 3 months after transplantation (n = 131). The major causes of death were malignancy (35.8%) and cardiac allograft vasculopathy (24.7%). No death related to acute rejection was reported after the first month of transplantation. Graft coronary artery disease was detected on angiography in 66 (50.3%), and 7 (5.3%) had retransplantation. Malignancies developed in 131 patients (48.1%), including skin cancers in 31 (23.6%), solid tumors in 26 (19.8%), and hematologic malignancies in 14 (10.6%). Severe renal function requiring dialysis or renal transplantation developed in 27 patients (20.6%). By multivariable analysis, the only pre-transplant risk factor found to affect long-term survival was a history of cigarette use ( p Conclusions Long-term survival at 15 years after cardiac transplantation remains excellent in the cyclosporine era. Controlling acute allograft rejection can be achieved but seems to carry a high rate of cancers and renal dysfunction. History of cigarette use affects significantly long-term survival in our study.

Background—Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice.Methods and Results—The entire coding sequences of 9 genes (MYH7,MYBPC3,TNNI3,TNNT2,MYL2,MYL3,TPM1,ACTC, andTNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients (≈63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (P=0.036). Moreover, a mutation was found in 15 of 25 index cases with “sporadic” hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients.Conclusion—These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testingMYBPC3andMYH7and then focus onTNNI3,TNNT2, andMYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.

Aims The aim of this paper is to report clinical characteristics, consequences, echocardiographic features, and pathological findings encountered in patients suffering from valvular disease associated with benfluorex exposure in a multicentre French registry. Methods and results Forty patients suffering from unexplained restrictive valvular disease with a previous exposition to benfluorex, a fenfluramine derivative, were identified from eight French university hospitals. Patients were mostly women (87.5%) with a mean age of 57 ± 9 years and high body mass index of 30 ± 7 kg/m²; 37.5% of them presented with severe heart failure symptoms (NYHA class III and IV). Benfluorex mean daily dose was 415 ± 131 mg with total therapy duration of 72 ± 53 months. Resulting cumulative dose was 910 ± 675 g. Common echocardiographic findings were leaflets and sub-valvular apparatus thickening and retraction. Aortic and mitral valve regurgitations resulting from leaflets loss of coaptation were the most frequent findings (87.5 and 82.5%) and were severe in 29 patients (72.5%). Multiple valve involvements were present in 31 cases (77.5%). Pulmonary arterial hypertension was identified in 20 cases (50%). Histopathological examination demonstrated abundant extra cellular matrix encasing the leaflets without modification of valve architecture. Fifteen patients (37.5%) underwent valvular surgery. Conclusion Benfluorex-related valvulopathy shares numerous characteristics with other drug-induced valvular disease. Clinical consequences may be serious with severe heart failure symptoms that may lead to surgical treatment.

PurposeCardiac resynchronisation therapy (CRT) is known to improve survival and to induce beneficial left ventricle (LV) remodeling in heart failure (HF) patients presenting with severe LV systolic dysfunction and prolonged QRS interval. Using those selection criteria, about 35 to 40% of patients remain non-responders to CRT. We assessed whether exercise inter-ventricular dyssynchrony could be a relevant index for the prediction of response to CRT.MethodsEighteen HF patients performed a semi-supine symptom-limited exercise echocardiography before device implantation. Inter-ventricular dyssynchrony, assessed by inter-ventricular mechanical delay (IVMD) in pulsed wave doppler, was recorded both at rest and peak exercise. We determined correlations between IVMD at exercise and cardiac output, mitral regurgitation, assessed by the effective regurgitant orifice area (ERO), and right ventricular (RV) longitudinal systolic function, assessed by tissue doppler imaging. We looked for correlations between those parameters and the degree of LV reverse remodeling at three months follow-up assessed by the percentage of change in LV end-sytolic volume (%ΔESV) and absolute value of change in ejection fraction (ΔLVEF).Results39% of patients were non-responders according to LV remodeling. Exercise-induced changes in IVMD only significantly correlated with RV longitudinal systolic function (r= - 0.602; p=0.01) at peak exercise. In a multivariate analysis by stepwise regression, IVMD at peak exercise was independently correlated with %ΔESV (β=0.418; p=0.01) and ΔLVEF (β=-0.563, p=0.03) at follow-up. Peak exercise ERO was the only other independent factor correlated with %ΔESV (β=0.808, p

Purpose Type II pulmonary hypertension (PH) is frequent in advanced HF patients. Initially passive, secondary to elevated left side filling pressures, PH can evolve to a reactive profile involving the pulmonary arterial vasculature, defined at right heart catheterization (RHC). When reactive PH remains fixed despite an aggressive reversibility protocol, heart transplantation is contraindicated. This study reports the experience of two cardiac transplant centres of open-label 3-months (3M) sildenafil (S) therapy, a selective phosphodiesterase inhibitor (PDE-5), in HF patients with PH, focusing on pulmonary hemodynamics at rest. Methods and Materials We conducted a retrospective review of HF patients evaluated for cardiac transplantation who received sildenafil therapy because of severe PH despite optimal medical therapy. We compared hemodynamic findings, including trans-pulmonary gradient (TPG), cardiac index (CI) and pulmonary vascular resistance(PVR) at baseline and after 3M of S. Results 37 advanced HF patients (NYHA III-IV, 86% male) with a mean age of 50±12 years and depressed LVEF (23±5%), received S for severe PH (mPAP 41±11mmHg). Compared to baseline, RHC resting values at 3M showed 19% increase in CI (1.6, 1.4–1.9 to 1.9, 1.6–2.6 l/min/m2, p=0.002) and 23% decrease in PVR (4.6, 3.2-6.0 to 3.2, 2.4–5.4 WU, p=0.01), without TPG change (−12%, 16 to 13 mmHg, p=0.09). sPAP, dPAP and PCWP were also unchanged. Amongst the patients with reactive PH at baseline (32/37), six evolved toward a passive PH profile at 3M and 14/18 of the fixed PH patients, had a reversible profile at 3M. Conclusions In advanced HF patients with type II PH, 3M of sildenafil therapy increased CI and decreased PVR on resting RHC. An aggressive reversibility protocol was able to modify reactive or fixed PH to a passive profile, leading to potential transplant candidacy for these patients. These results suggest a strong implication of NO and PDE pathway in severePH secondary to HF.

Resume Les endocardites a hemocultures negatives posent un probleme diagnostique, therapeutique et pronostique. Nous rapportons le cas d’un homme de 57 ans avec pour seul antecedent un rhumatisme articulaire aigu. En aout 2000, decouverte d’une thrombose veineuse surale du membre inferieur droit sans facteur favorisant retrouve. Mise en route d’un traitement par AVK. En octobre 2000, mise en evidence d’une occlusion du tronc tibio-peronier droit et d’une thrombose suspendue de l’artere poplite gauche dans un contexte de claudication du membre inferieur droit. Une EI est suspectee apres 2 autres episodes emboliques et sur l’antecedent rhumatismal. Ce diagnostic est confirmee par ETO : fuite aortique associee a des vegetations de 8 mm. Les hemocultures sont negatives. Un interrogatoire policier a la recherche d’une porte d’entree fait suspecter une maladie de Whipple devant la notion d’arthralgies associees a une diarrhee intermittente avec perte de poids et ceci malgre des biopsies jejunales negatives. Le diagnostic sera pose sur la valvule aortique resequee pour remplacement par homogreffe et sur la relecture des thrombi reseques anterieurement. Examen anatomopathologique : reaction inflammatoire a predominance macrophagique avec inclusions PAS positives cytoplasmiques. Confirmation par immunohistochimie avec Ac anti-tropheryma whipplei et par PCR. Conclusion La maladie de Whipple doit etre evoquee devant toute EIHN avec contexte evocateur (diarrhee, perte de poids, arthralgies). L’examen anatomopathologique reste primordial et peut etre complete par biologie moleculaire. L’atteinte cardiaque au cours du Whipple n’est pas rare. Le pronostic reste sombre si une antibiotherapie adaptee et au long cours n’est pas mise en place rapidement.

MOTS CLES Benfluorex ; Fibrose valvulaire ; Amphetamines ; A 57-year-old woman was referred for dyspnoea during mild exercise, especially during the past year. Electrocardiogram and chest X-ray demonstrated no significant anomaly. Ntpro brain natriuretic peptide was moderately elevated to 319 ng/L (range: 0—290 ng/L). Echocardiographic examination showed normal left ventricle function and anatomy, mild regurgitations of the aortic and mitral valves and a severe regurgitation of the tricuspid valve (Figs. 1 and 2), with an estimated systolic pulmonary pressure of 60mmHg. Themechanism of the valvular regurgitations corresponded to valvular fibrosis and subsequently restriction motion. Right heart catheterization confirmed pulmonary arterial hypertension with normal pulmonary wedge pressure and cardiac output. Thoracic tomodensitometry ruled out pulmonary embolism. There was also no clinical or biological evidence for a carcinoid syndrome. The patient had no previous medical history, but she had taken benfluorex (150mg tid) for the past 8 years because of excessive weight (159 cm, 82 kg) and hypertriglyceridaemia. In addition to withdrawal of the drug, and because of elevated right atrial pressure, we

International audience; Background Hereditary transthyretin cardiac amyloidosis (mTTR-CA) is a hypertrophic cardiomyopathy with challenging diagnosis and poor prognosis. The prevalence of m-TTR in patients with increased left ventricular wall thickness (LVWT) is unknown. Methods Prospective and consecutive multicenter study with systematic genetic screening for mTTR in adult patients with LVWT ≥15mm included in cardiology primary clinics. Results 298 patients were genotyped of whom 23% were African descendant. The median (IQR) age was 62(50,74), 74% were men and 36% were in NYHA class III-IV. The median of maximal LV thickness was 18 (16, 21)mm.17 patients had TTR mutation (5.7%) of whom 15 (5.0) had confirmed mTTR-CA. All the mTTR-CA were ≥55years meaning that the prevalence of mTTR-CA was 8.3% above this age. Of the 15 with mTTR-CA, 8 were Africans and 6 Caucasians. In Africans ≥55 years, the prevalence was 22% and reached 35% in those over 65 years. The most frequent mutations were V142I (8), V50M (2) and I127V (2). When adjusted to age, neuropathy (OR=20.1; 95%-CI, 5.86-69.4; P